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PHYTOCHEMISTRY AND – Occurrence and Function of Natural Products in – Michael Wink

OCCURRENCE AND FUNCTION OF NATURAL PRODUCTS IN PLANTS

Michael Wink Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, INF 364, 69120 Heidelberg, Germany

Keywords: Secondary , ecological functions, defense compounds, signal compounds, evolution, chemotaxonomy, pharmacology, toxicology, endophytic fungi, horizontal gene transfer, transport, storage

Contents

1. Classes and Numbers of Secondary Metabolites (SM) 2. Occurrence and Properties of Major Groups of SM 3. Physiology of Secondary : Biosynthesis, Transport and Storage of SM 4. Ecological Roles of SM 5. Molecular Modes of Action of SM 6. Chemosystematics of Plants and Distribution Patterns of SM 7. Origins and Evolution of Secondary Metabolism 8. Conclusions Glossary Bibliography Biographical sketch

Summary Secondary metabolites (SM) occur in plants in a high structural diversity. A typical feature of secondary metabolites is their storage as complex mixtures in relatively high concentrations, sometimes in organs which do not produce them. Some SM are stored as inactive “prodrugs” that are enzymatically activated in case of danger (wounding, ). Biochemical and physiological features of secondary metabolism are strongly correlated with its function: SM are not useless waste products but important means of plants for defense against , microbes (, fungi) and viruses. Some SM also functions as signal molecules to attract pollinating arthropods or seed- dispersing . Land plants have evolved SM with a wide repertoire of biochemical and pharmacologicalUNESCO properties. Many –SM inEOLSSteract with proteins, DNA/RNA and/or biomembranes. Some of the interactions with molecular targets are highly specific, others have pleiotropicSAMPLE properties. All plants CHAPTERSproduce secondary metabolites. Whereas some SM have a taxonomically restricted distribution, very often the same SM also occurs in other plant groups which are not phylogenetically related. How to explain the patchy distribution? Theoretically, the occurrence of a SM in unrelated taxa may be due to convergent evolution. Alternatively, the genes encoding the of secondary metabolism might be widely distributed in the plant but switched on or off in a certain phylogenetic context. The analysis of nucleotide and sequences, provide evidence that most of the genes, which encode key enzymes of SM biosynthesis have indeed a wide distribution in the plant kingdom. It is speculated that these genes were introduced into the plant genome during early evolution by horizontal gene

©Encyclopedia of Support Systems (EOLSS) AND PHARMACOGNOSY – Occurrence and Function of Natural Products in Plants – Michael Wink

transfer, i.e. via bacteria that developed into mitochondria and chloroplasts. A patchy distribution can also be due to the presence of endophytic fungi, which are able to produce SM. The profile of plant secondary metabolites in a given plant is thus the result of a complex process that had evolved over the last 500 million years.

1. Classes and Numbers of Secondary Metabolites

A typical characteristic of plants and other sessile organisms, which cannot run away when attacked by enemies or which do not have an to ward off pathogens, is their capacity to synthesize an enormous variety of low molecular weight compounds, the so-called secondary metabolites (SM) or natural .

Type of secondary Approximate numbers* Nitrogen-containing SM 21000 Non-protein amino acids (NPAAs) 700 Amines 100 Cyanogenic 60 Glucosinolates 100 Alkamides 150 Lectins, peptides, polypeptides 2000 SM without nitrogen Monoterpenes including iridoids (C10) ** 2500 Sesquiterpenes C15)** 5000 Diterpenes (C20)** 2500 Triterpenes, , saponins (C30, C27)** 5000 Tetraterpenes (C40)** 500 Flavonoids, 5000 , lignin, coumarins, lignans, 2000 Polyacetylenes, fatty acids, waxes 1500 Anthraquinones and other 750 , organic acids 200

Table 1. Numbers of secondary metabolites reported from higher plants *approximateUNESCO number of known structures; – **t EOLSSotal number of exceeds 22000 at present. More than 100SAMPLE 000 SM have been identified CHAPTERS by phytochemists, including many nitrogen-free (such as , saponins, polyketides, phenolics and polyacetylenes) and nitrogen-containing compounds (such as alkaloids, amines, cyanogenic glycosides, non-protein amino acids, glucosinolates, alkamides, peptides and lectins) (Table 1, Figure 1). All plants produce SM and usually store several major compounds, usually from different structural classes and biochemical pathways, which are commonly accompanied by dozens of minor components. It is typical to find complex mixtures, which differ from organ to organ, sometimes between individual plants and regularly between . Within a single plant species 5000 to 20000 individual primary and

©Encyclopedia of Life Support Systems (EOLSS) PHYTOCHEMISTRY AND PHARMACOGNOSY – Occurrence and Function of Natural Products in Plants – Michael Wink

secondary compounds may be produced, although most of them as trace amounts which usually are overlooked in a analysis.

Figure 1. Structures of selected secondary metabolites.

2. Occurrence and Properties of Major Groups of SM

Alkaloids are widely distributed in the plant kingdom (especially angiosperms) and represent the largest group of SM that contain one or several nitrogen atoms either in a ring structureUNESCO (true alkaloids) or in a side – chain EOLSS (pseudoalkaloids). Chemically, alkaloids behave as a base; they are uncharged at alkaline pH (>11) and protonated under physiological conditions.SAMPLE The majority of alka CHAPTERSloids have been found to be derived from amino acids, such as tyrosine, , anthranilic acid, /tryptamine, ornithine/arginine, lysine, histidine and nicotinic acid. However, alkaloids may be derived from other precursors such as purines in case of caffeine, terpenoids, which become “aminated” after the main skeleton has been synthesized, i.e. aconitine or the steroidal alkaloids, such as are found in the Solanaceae and Liliaceae. Alkaloids may also be formed from acetate-derived polyketides, where the amino nitrogen is introduced as in the hemlock , coniine. Depending on the ring structures, alkaloids are subdivided into pyrrolidine, piperidine, pyrrolizidine, quinolizidine, isoquinoline, protoberberine, aporphine, morphinane, quinoline, acridone, indole,

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monoterpene indole, diterpene or alkaloids. The biosynthetic pathways of the main groups of alkaloids have already been elucidated at the and gene level. Alkaloid are infamous as and certainly serve mainly as defense chemicals against predators (herbivores, carnivores) and to a lesser degree against bacteria, fungi and viruses. Alkaloids and amines often affect neuroreceptors in animals as agonists or antagonists, or they modulate other steps in neuronal , such as ion channels or enzymes, which take up or degrade or second messengers. Since alkaloids often derive from the same amino acid precursor as the neurotransmitters acetylcholine, serotonin, noradrenaline, dopamine, gamma aminobutyric acid (GABA), glutamic acid or histamine, their structures can frequently be superimposed on those of neurotransmitters. They thus share functional pharmacological groups. Other alkaloids are mutagenic in that they intercalate DNA, alkylate DNA, induce apoptosis or inhibit processing enzymes. It is apparent that the of most alkaloids is correlated with their interactions with a particular molecular target. Non-protein amino acids (NPAAs) are abundant in seeds, leaves and roots of legumes (Fabaceae) and in some monocots (Alliaceae, Iridaceae, Hyacinthaceae), but also occur in Cucurbitaceae, Euphorbiaceaee, Resedaceae, Sapindaceae, and Cycadaceae. They can be considered as structural analogues to one of the 20 protein amino acids. NPAAs frequently block the uptake and transport of amino acids or disturb their biosynthetic feedback regulations. Some NPAAs are even incorporated into proteins, since transfer ribonucleic acid (tRNA) transferases cannot usually discriminate between a protein amino acid and its analogue; resulting in defective or malfunctioning proteins. Other NPAAs interfere with neuronal signal transduction or enzymatic processes. NPAAs often accumulate in seeds where they serve as repellent nitrogen storage molecules, which are recycled during growth of the seedling after germination. Cyanogenic glycosides have been recorded from more than 2000 plant species; they are especially abundant in Rosaceae, Fabaceae, Euphorbiaceae, Caprifoliaceae, Poaceae, Linaceae, Lamiaceae, Passifloraceae, Sapindaceae, Juncaginaceae and . Cyanogens are stored in the vacuole of seeds, leaves and roots as prefabricated allelochemicals (“prodrug” principle). If decomposition occurs due to wounding by a herbivore or a pathogen, then a β-glucosidase comes into contact with the cyanogenic glucosides, which are split into a sugar and a nitrile moiety that is further hydrolyzed to hydrocyanic acid (HCN) and an aldehyde. HCN binds to cytochrome oxidase UNESCOand therefore effectively blocks – mitochondrial EOLSS respiration; in consequence adenosine triphosphate (ATP) production is blocked. Therefore, HCN functions as a strong poison inSAMPLE most animals. CHAPTERS Glucosinolates also function as prefabricated vacuolar defense compounds. They occur in seeds, leaves and roots in a phylogenetically related complex, the Brassicales, which comprises the Brassicaceae, Capparaceae, Tropaeolaceae, Resedaceae, Moringaceae, and others. The glucosinolates are a precursor for the active mustard oils, which are released after cleavage by myrosinase. Mustard oils are highly lipophilic and can disturb the fluidity of biomembranes and bind to various enzymes, receptors or other , such as DNA (thereby exhibiting a substantial antimicrobial effect). Terpenes have a basic C5-unit (isopentenyl pyrophosphate or dimethylallyl pyrophosphate) as a building block and can be subdivided into monoterpenes (C10),

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sesquiterpenes (C15), diterpenes (C20), triterpenes (C30), tetraterpenes (C40) and polyterpenes. Steroids are derived from triterpenes. Mono-, sesqui-, di- and triterpenes occur in most plant families; they are usually highly hydrophobic substances and are stored in resin ducts, oil cells or glandular trichomes. Most of them readily interact with biomembranes and membrane proteins. They can increase the fluidity of the membranes, which can lead to uncontrolled of ions and metabolites, modulation of membrane proteins and receptors or even to leakage, resulting in cell death. This membrane activity is rather non-specific; therefore, terpenes show cytotoxic activities against a wide range of organisms, ranging from bacteria and fungi to insects and vertebrates. Many terpenes are even effective against membrane enclosed viruses. Even if the concentrations were not critical for a large vertebrate herbivore, -rich is usually avoided, since these terpenes would inhibit the growth of rumen , which are important for the breakdown of . A number of terpenes have additional properties because their structures figure as analogues to natural substrates, (e.g. steroidal hormones, sex hormones, ecdysone, juvenile ) or neurotransmitters. Sesquiterpene lactones, which are common in Asteraceae and a few other families (Apiaceae, Magnoliaceae, Menispermaceae, Lauraceae, and ferns), can bind to proteins with SH- groups and are therefore pharmacologically active. Several diterpenes are quite toxic; phorbol esters (present in Euphorbiaceae and Thymelaeaceae) activate protein kinase C and therefore cause severe inflammation. Grayanotoxin I (or andromedotoxin), which is common in Ericaceae is a potent inhibitor of sodium channels and thus a strong . Saponins are the glycosides of triterpenes or steroids and include the group of cardiac glycosides and steroidal alkaloids. Steroid saponins are typical for monocots, especially for Dioscoreaceae, Melanthiaceae/Trilliaceae, Liliaceae, Agavaceae, Asparagaceae, Ruscaceae, Zingiberaceae, Alliaceae, Poaceae and Smilacaceae; they are less frequent in dicots (Fabaceae, Scrophulariaceae, Plantaginaceae, Solanaceae, Araliaceae). Triterpene saponins are abundant SM in Caryophyllaceae, Ranunculaceae, Phytolaccaceae, Chenopodiaceae, Styracaceae, Hippocastanaceae, Theaceae, Fabaceae, Apiaceae, Araliaceae, Asteraceae, Aquifoliaceae, Rosaceae, Polygalacdeae, Chenopodiaceae, Cucurbitaceae, Rhamnaceae, Primulaceae, Poaceae and Sapotaceae. They are absent in gymnosperms. Some saponins are stored as bidesmosidic compounds in the vacuole, which are cleaved to the active monodesmosidic compounds by β- glucosidase or an upon wounding-induced decompartmentation. Monodesmosidic saponins are amphiphilic compounds, which can complex in biomembranesUNESCO with their lipophilic – terpenoidEOLSS moiety and bind to surface glycoproteins and glycolipids with their sugar side chain. This leads to a severe tension of the biomembrane and leakage. This activity can easily be demonstrated with erythrocytes, whichSAMPLE lose their hemoglobi nCHAPTERS (haemolysis) when in contact with monodesmosidic saponins. This membrane activity is rather unspecific and effects a wide set of organisms from microbes to animals. Therefore, saponins have been used in traditional as anti-infecting agents. Some saponins have additional functional groups, such as cardiac glycosides (carrying a 5 or 6 membered cardenolide or bufadienolide ring), which enable them to inhibit one of the most important molecular targets of animal cells, the Na+-, K+-ATPase. Na+-, K+- ATPase builts up Na+ and K+ gradients which are essential for transport activities of cells and neuronal signaling. Therefore, cardiac glycosides are strong which

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cause death through cardiac and respiratory arrest. Among steroidal glycosides, the cucurbitacins (occurring in members of the Cucurbitaceae) express substantial cytotoxic activities; they may interfere with the formation of the mitotic spindle during cell division. Flavonoids and phenylpropanoids (including coumarins, furanocoumarins, catechins and tannins) are widespread in plants. They exhibit a wide range of biological activities. In several instances, they act as analogues of cellular signal compounds or substrates. Afflicted mechanisms range from and leukotriene formation, enzyme inhibition, estrogenic properties (coumarins, isoflavones, stilbenes) to DNA alkylation (e.g. by furanocoumarins). These molecules usually have several phenolic hydroxyl groups in common, which can dissociate in negatively charged phenolate ions under physiological conditions. Phenolic hydroxyl groups form hydrogen and ionic bonds with proteins and peptides. The higher the number of hydroxyl groups, the stronger the astringent and denaturing effect. Tannins inhibit enzymatic activities very effectively; however, most digestive enzymes of herbivores have apparently adapted to tannins during evolution and are less sensitive than other enzymes. are present in most drugs used in phytotherapy and apparently are responsible for a wide array of pharmacological properties, including antioxidant, anti-inflammatory, sedating, wound- healing, antimicrobial and antiviral activities. Polyketides include anthraquinones, hydro- and naphthoquinones. Hydroquinones are typical for Ericaceae, naphthoquinones for Droseraceae, Iridaceae, Bignoniaceae, Juglandaceae, and Balsaminaceae. Anthraquinones are charactersitic for Polygonaceae, Rhamnaceae, Fabaceae, Rubiaceae, Hypericaceae, Scrophulariaceae, Asphodelaceae, and Liliaceae. Anthraquinones produce severe diarrhoea in vertebrates by interfering with intestinal Na+, K+-ATPase and adenylyl cyclase. The anthraquinones can intercalate DNA and appear to be mutagenic. Polyacetylenes are characteristic for Apiaceae, Araliaceae and Asteraceae. Thiophenes, which are sulphur-containing polyacetylenes occur in the Asteraceae genera Dahlia, Eclipta, Flaveria, Porophyllum, Rudbeckia, Tagetes, and Tessaria. Because of the triple bonds these SM are highly reactive (often activated by light) and can interact with biomembranes and proteins. They are highly cytotoxic and sometimes neurotoxic; they also show antimicrobial activities. - - - UNESCO – EOLSS

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Bibliography

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APG III (2009). An update of the Angiosperm Phylogeny Group classification for the orders and families of flowering plants: APG III. Bot. J. Linnean Soc. 161: 105-121. [This important work shows the phylogeny and new systematics of angiosperms]. Brown, K. and Trigo, J.R. (1995). The ecological activity of alkaloids, in The Alkaloids (ed. G.A. Cordell), Vol. 47, pp. 227–354. [This work provides an authoritative review on the ecological functions of alkaloids]. Cassady, J.M., Chan, K.K., Floss, H., and Leistner, E. (2004). Recent developments in the maytansinoid antitumor agents. Chem. Pharm. Bull. 52, 1-26, 2004. [This work shows that maytansinoids are produced by ]. Cipollini, M.L. and Levey, D.J. (1997). Secondary metabolites of fleshy vertebrate-dispersed fruits: adaptive hypotheses and implications for seed dispersal. Amer. Naturalist, 150 346–73. [This review reports on the role of SM to attract seed dispersing animals]. Deus-Neumann, B. and Zenk, M. H. (1984). A highly selective alkaloid uptake system in vacuoles of higher plants. Planta, 162 250–60. [This work postulates the presence of a proton-alkaloid antiporter at the tonoplast]. Dewick, P.M. (2002). Medicinal Natural Products. A biosynthetic approach. 2nd ed., Wiley, New York.[Textbook with detailed information on the biosynthesis of SM]. Duffey, J. (1980). Sequestration of plant natural products by insects. Annu. Rev. Entomol., 25 447-477. [Review on the sequestration of SM by insects]. Ehrlich, P.R. and Raven, P.H. (1964). Butterflies and plants: a study of coevolution. Evolution, 18 586– 608. [Classical paper highlighting the importance of SM as defense compounds]. Eyberger, A.L., Dondapati, R., and Porter, J.R.J. (2006). fungal isolates from Podophyllum peltatum produce podophyllotoxin. J. Nat Prod 69, 1121-1124. [This work shows that podophyllotoxin is produced by endophytes]. Facchini, P. (2001). Alkaloid biosynthesis in plants: biochemistry, cell biology, molecular regulation, and metabolic engineering applications. Annu. Rev. Plant Physiol. Plant Mol. Biol. 52 29-66. [Authoritative review of alkaloid biochemistry]. Facchini, P.J., Bird, D.A., and St-Pierre, B. (2004). Can Arabidopsis make complex alkaloids? Trends Plant Sci., 9 116-122 [The author discuss the finding, that Arabidopsis has many genes, that are similar to those in alkaloid plants, although it does not produce alkaloids]. Fraenkel, G. (1959). The raison d’être of secondary substances. Science, 129 1466–70. [Classical paper highlighting the importance of SM as defense compounds]. Harborne, J.B. (1993). Introduction to Ecological Biochemistry, 4th Edn, Academic Press, London. [Classic textbook highlighting the importance of SM as defense compounds]. Harborne, J.B. and Turner, B.L. (1984). Plant Chemosystematics. Academic Press, London. [Classic textbook highlighting the importance of SM as taxonomic markers]. Hartmann,UNESCO T. (2007). From waste products to –ecochemicals: EOLSS Fifty years research of plant secondary metabolism. Phytochemistry 68, 2831-2846. [Review discussing the hypothesis that SM are defense compounds and notSAMPLE waste products]. CHAPTERS Jörgensen, K., Rasmussen, A.V., Morant, M., Nielsen, A.H., Bjanrholt, N., Zagrobelny, M., Bak, S., and Möller, B.L. (2005). Metabolon formation and metabolic channeling in the biosynthesis of plant natural products. Curr. Opin. Plant Biol. 8 280-291. [Important review on metabolism of SM]. Kusari, S., Lamshöft, M., Zühlke, S., and Spiteller, M., (2008). An endophytic from Hypericum perforatum that produces hypericin. J. Nat. Prod. 71, 159-162. [This work shows that hypericin is produced by endophytes]. Kutchan, T.M. (2005). A role for intra- and intercellular translocation in natural product biosynthesis. Curr. Opin. Plant Biol., 8 292-300. [Important review on the transport of SM]. Levin, D.A. (1976). The chemical defences of plants to pathogens and herbivores. Annu. Rev. Ecol. Syst., 7 121–59. [Classical paper highlighting the importance of SM as defense compounds].

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Mann, J. (1992). Murder, Magic and Medicine. Oxford University Press, London. [Interesting monograph on the utilisation of SM by humans]. Martinoia, E. Klein, M. Geisler, M. Bovet, L. Forestier, C. Kolukisaoglu, Ü., Müller-Röber, B., and Schulz, B. (2002) Multifunctionality of plant ABC transporters - more than just detoxifiers. Planta, 214 345-355. [Review describing the evidence and functions for ABC transporters in plants]. Matile, P. (1978). Biochemistry and function of vacuoles. Annu. Rev. Plant Physiol., 29 193–213. [Classical paper highlighting the importance of the vacuole to store SM]. Matile, P. (1980). The ‘mustard oil bomb’: compartmentation of myrosinase systems. Biochem. Physiol. Pflanzen, 175 722–31. [Classical paper highlighting the importance of the vacuole to store glucosinolates and the role of compartimentation]. Memelink, J. (2005). The use of genetics to dissect plant secondary pathways. Curr. Opin. Plant Biology, 8 230-235. [Review on the progress of molecular biology to elucidate the biosynthesis of SM]. Oksman-Caldentey, K.-M., Häkkinen, S.T., and Rischer, H. (2007). Metabolic engineering of the alkaloid biosynthesis in plants: Functional genomic approaches, in Applications of Plant Metabolic Engineering (eds. Verpoorte, R., Alfermann, A.W. and Johnson, T.S.). Springer, Heidelberg, pp. 109-143. [Review on the progress of molecular biology to elucidate the biosynthesis of SM]. Puri, S.C., Verma, V., Amna, T., Qazi, G. N., and Spiteller, M. (2005). An endophytic fungus from Nothapodytes foetida that produces . J. Nat. Prod. 68, 1717-1719. [This work shows that camptothecin is produced by endophytes]. Ralphs, M.H., Creamer, R., Baucom, D., Gardner, D.R., Welsh, S.L., Graham, J.D., Hart, C., Cook, D., and Stegelmeier, B.L. (2008). Relationship between the endophyte Embellisia spp. and the toxic alkalod swainsonine in major locoweed species (Astragalus and Oxytropis). J. Chem. Ecol. 34, 32-38. [This work shows that camptothecin is produced by endophytes]. Rea, P.A. (2007). Plant ATP-binding cassette transporters. Annu. Rev. Plant Biol., 58 347-375. [Review describing the evidence and functions for ABC transporters in plants]. Roberts, M.F. and Wink, M. (1998). Alkaloids:- Biochemistry, Ecological Functions and Medical Applications. Plenum, New York. [Monographs discussing the biochemistry, physiology, and ecology of alkaloids]. Sakai, K., Shitan, N., Sato, F., Ueda, K., and Yazaki, K. (2002). Characterization of berberine transport into japonica cells and the involvement of ABC protein, J. Exp. Bot. 53 1879-1886. [Paper describing the evidence and function of ABC transporters for the transport of berberine] Seigler, D.S. (1998). Plant Secondary Metabolism. Kluwer, Norwell. [Authoritative textbook on the biochemistry and physiology of SM]. Stierle, A., Strobel, G. A. and Stierle, D. (1993). Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew. Science, 260 214 - 216. Swain, T. (1977). Secondary compounds as protective agents. Annu. Rev. Plant Physiol., 28 479501. [Classical UNESCOpaper highlighting the importance of SM– as defenseEOLSS compounds]. Teuscher, E. and Lindequist, U. (2010). Biogene Gifte, Fischer, Stuttgart. [Authoritative textbook on the biochemistry and physiologySAMPLE of toxic SM]. CHAPTERS Verpoorte, R., Alfermann, A.W. and Johnson, T.S. (2007). Applications of Plant Metabolic Engineering. Springer, Heidelberg. [Monograph on the progress of molecular biology to elucidate the biosynthesis of SM and to produce SM in cell cultures or recombinant microorganisms]. Wink, M. and Van Wyk, BE. (2008). Mind-altering and poisonous plants of the world. BRIZA, Pretoria (SA). [Illustrated handbook on poisonous plants, poisonous SM and their modes of action]. Wink, M. (1988). Plant breeding: importance of plant secondary metabolites for protection against pathogens and herbivores. Theor. Appl. Gen., 75 225–33. [Classical paper highlighting the importance of SM as defense compounds].

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Wink, M. (1992). The role of quinolizidine alkaloids in plant insect interactions, in Insect-Plant Interactions (ed. E.A. Bernays), CRC Press: Boca Raton, Vol. IV, pp. 133–69. [Classical paper highlighting the importance of quinolizidine alkaloids as defense compounds]. Wink, M. (1993). The plant vacuole: a multifunctional compartment. J. Exp. Bot., 44 231–46. [Review highlighting the importance of the vacuole to store SM]. Wink, M. (1993a). Allelochemical properties and the raison d’être of alkaloids, in The Alkaloids (ed. G. Cordell), Academic Press, Orlando, Vol. 43, 1–118. [This work provides an authoritative review on the ecological functions of alkaloids]. Wink, M. (1997). Compartmentation of secondary metabolites and xenobiotics in plant vacuoles. Adv. Bot. Res., 25 141–69. [Review highlighting the importance of the vacuole to store SM] Wink, M. (2000). Interference of alkaloids with neuroreceptors and ion channels, in Bioactive Natural Products, (Atta-Ur-Rahman ed.), Elsevier, pp. 1–127. [This work provides an authoritative review on the neuropharmacology of alkaloids]. Wink, M. (2003). Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective. Phytochemistry 64, 3-19. [Review discussing the evidence that the genes of SM are probably widely distributed in plants and that a simple chemotaxonomic approach is naïve]. Wink, M. (2007). Molecular modes of action of cytotoxic alkaloids- From DNA intercalation, spindle poisoning, topoisomerase inhibition to apoptosis and multiple drug resistance, in The Alkaloids, (ed. G. Cordell), Academic press, San Diego, vol. 64, 1-48. [This work provides an authoritative review on the molecular pharmacology of alkaloids]. Wink, M. (2008). Evolutionary advantage and molecular modes of action of multi-component mixtures used in phytomedicine. Current Drug Metabolism 9, 996-1009. [This work describes the molecular mode of actions of SM and discusses the importance of complex mixtures]. Wink, M. (2008b). Plant Secondary Metabolism: Diversity, Function and its Evolution. Natural Products Communications 3, 1205-1216. [This review discusses the origin and function of secondary metabolism and the importance of endophytes]. Wink, M., Botschen, F., Gosmann, C., Schäfer, H. and Waterman, P. G. (2010] Evolution and origin of plant secondary metabolism-Implications for chemotaxonomy. In Wink M Biochemistry of plant secondary metabolism. Blackwell-Wiley-VCH, 2010 [Review discussing the evidence that the genes of SM are probably widely distributed in plants and that a simple chemotaxonomic approach is naïve]. Wink, M. (2010). Biochemistry of plant secondary metabolism, Wiley-Blackwell Annual Plant Reviews 2nd ed., APR Volume 40, 2010 [Monograph with detailed chapters on the biosynthesis of SM]. Wink, M. (2010). Functions and Biotechnology of plant secondary metabolites. Wiley-Blackwell Annual Plant Reviews vol 39, 2010, 2nd ed. [Monograph with detailed chapters on the functions, pharmacology and biotechnology of SM]. Winkel, B.S.J. (2004). Metabolic channelling in plants. Annu. Rev. Plant Biol. 55 85-107. [Review on the importanceUNESCO of channeling in SM biosynthesis]. – EOLSS Wu, S. and Chappell, J. (2008). Metabolic engineering of natural products in plants; tools of the trade and challenges for the future. Curr. Opin. Biotechnol. 19 145-152. [Review on the progress of molecular biology to elucidateSAMPLE the biosynthesis of SM and to produce CHAPTERS SM in recombinant microorganisms]. Yazaki, K. (2006). ABC transporters involved in the transport of plant secondary metabolites, FEBS Letters, 580 1183 – 1191. [Review describing the evidence and functions for ABC transporters in plants]. Zenk, M.H. and Juenger, M. (2007). Evolution and current status of the phytochemistry of nitrogenous compounds, Phytochemistry, 68 2757-2772. [Review on the progress in biosynthesis of alkaloids in the last 30 years].

Biographical Sketch

Michael Wink was born in 1951 in Esch-Bad Münstereifel near Bonn (Germany). He studied biology, and statistics at the University of Bonn and obtained his “Diplom” in 1977. His PhD work was

©Encyclopedia of Life Support Systems (EOLSS) PHYTOCHEMISTRY AND PHARMACOGNOSY – Occurrence and Function of Natural Products in Plants – Michael Wink

on the biochemistry and physiology of quinolizidine alkaloids; he obtained a Dr. rer. nat. in 1980 from the Technical University of Braunschweig (Germany). After 4 years as a lecturer (Hochschulassistent C1) he passed his “Habilitation” and got a Dr. rer. nat. habil. from Technical University of Braunschweig (Germany) in 1984/85. He was awarded a Heisenberg- fellowship from the German Science Foundation (DFG) in 1985 which he used to spend 6 months at the Max-Planck-Institute of Plant Breeding at Cologne (Germany). In 1986 he joined the “Gene Centre” of the University of Munich. In 1988 he accepted a chair for “Pharmaceutical Biology” at the University of Mainz and a year later a full professorship at Heidelberg University at Heidelberg (Germany). He is head of the Department Pharmaceutical Biology at the Institute of Pharmacy and Molecular Biotechnology. At Heidelberg University he served several terms of office as dean, vice dean or student dean and head of department. He was visiting professor at the universities of Cordoba (Argentina), Nanjing (China) and Hat-Yai (Thailand) and was offered an Honorary professorship of the University of Harbin (China). He runs a large research group, working on natural products, their analytics, function and pharmacology, biotechnology and evolution (phylogeny, molecular ). He has published more than 20 books or monographs and more than 500 papers in peer-reviewed international journals. Prof. Dr. Michael Wink. He is a member of several professional societies of phytochemistry, medicinal plants, evolution, botany, pharmacy and ornithology.

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